Engineers seek to improve vascular grafts

4th December 2006

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New biomaterials have been developed by biomedical engineers at Washington University to help recruit endothelial cells to the inner surfaces of vascular grafts and actively protect against blood clotting.

A team led by Dr Donald Elbert, assistant professor of biomedical engineering at Washington University, Washington DC, USA, synthesised the new materials, made from about 50% synthetic polymers and 50% protein. The polymer portion of the materials is a derivative of polyethylene glycol that was initially synthesised by Washington University graduate student Evan Scott. When a solution of the polymer is mixed with protein at the correct ratio, a chemical reaction leads to the formation of a water-swollen hydrogel.

According to the researchers, the materials perform a variety of functions, including limiting protein activation, providing cell adhesion cues to the endothelial cells, and delivering molecules that enhance endothelial cell migration and survival. The polymer portion limits the activation of blood clotting proteins normally associated with artificial materials, while the protein portion traps a signalling molecule that promotes endothelial cell migration and survival. Endothelial cells grow on the surface of the materials due to the presence of chemically synthesised molecules that specifically bind to adhesion receptors on the cell surface.

In a recent study published in the journal Biomacromolecules, graduate student Bradley K Wacker demonstrated that the migration speed of endothelial cells on the materials doubles when the signalling lipid sphingosine 1-phosphate (S1P) is delivered from the protein part of the material. S1P is a small molecule that is used for intercellular communication in the body. It interacts with receptors on endothelial cells to promote migration and survival, while limiting the migration of cells in the middle portion of the artery that sometimes cause narrowing of blood vessels.

“The challenges were unique, since the need for a lipid delivery system hadn’t been previously considered,” said Elbert.

Lipid delivery system

S1P is critical in the development of the vascular system, but it is also active in other parts of the body. For example, it is critical for the maturation of lymphocytes. Thus, Elbert and colleagues are working to localise the effects of the potent signalling lipid. The lipid is released over time from the materials but the endothelial cells sitting on the materials are the first cells to see the lipid. Afterwards, the lipid is quickly diluted and its effects are minimised.

Elbert believes that the delivery of S1P from these materials may prove to be particularly useful in conjunction with other factors that are currently being studied for therapeutic angiogenesis. Graduate student Shannon Alford has found that the effect of S1P delivery might be amplified by other stimuli such as shear stress or vascular endothelial growth factor. One particularly promising avenue is to synthesise the active S1P following implantation, by immobilising within the material the enzyme that normally produces S1P within the body. Biomedical engineering graduate student Megan Kaneda first cloned and expressed this enzyme in a manner that allows its incorporation within the material.

“This is a really unique opportunity in the field of drug delivery because we aren’t limited by the amount of drug that can be loaded in the material,” Elbert said. “We are able to take advantage of the fact that the precursor to S1P is already present in the bloodstream.”

Biomedical engineering graduate student Shannon Alford working in the laboratory with her advisor Donald Elbert, Ph.D., assistant professor of biomedical engineering. Alford and Elbert are part of a team that has developed new biomaterials that improve vascular grafts by greatly reducing the risk of blood clotting